Mechanisms of neuronal death in brain aging and alzheimer's disease: Role of endocrine-mediated...

Mechanisms of Neuronal Death in Brain Aging and Alzheimer’s Disease: Role of Endocrine-Mediated Calcium Dyshomeostasis

Philip W. Landfield,‘ Olivier Thibault, ’ Mary L. Mazzanti, ‘ Nada M. Porter,‘ and D. Steven Kerr2

’ Department of Pharmacology, University of Kentucky, College of Medicine, MS-305 Medical Center, Lexington, Kentucky 40536-0084; and *Department of Psychology, University of Otago, Dunedin, New Zealand

SUMMARY

This paper reviews evidence that brain aging and Alz- heimer’s disease (AD) are somehow closely related and that the hippocampus (CA1) is highly vulnerable to cell loss under both conditions. In addition, two current lines of evidence on the mechanisms of hippocampal cell loss with aging are considered, including studies of neuronal calcium dysregulation and studies of cumulative glucocorticoid (CC) neurotoxicity. Moreover, recent electrophysiological studies have shown that excess glucocorticoid activation of hippocampal neurons increases the influx of calcium through voltage-activated calcium chan-

nels. Second messenger systems may mediate the steroid modulation of calcium channels. Therefore, it is hypothe- sized that excess glucocorticoid activation and neuronal calcium dysregulation may be two phases of a single process that increases the susceptibility of neurons to neurodegeneration during aging and Alzheimer’s disease.

Keywords: brain aging, glucocorticoids, calcium regulation, hippocampus, neuron death, calcium potentials, calcium currents, Alzheimer’s Disease.

0 1992 John Wiley & Sons, Inc.

NEURON LOSS IN BRAIN AGING AND ALZHEIMER’S DISEASE (AD)

It has been well established in quantitative studies of human postmortem tissues that neocortical neurons exhibit a substantial decrease in density as a function of normal aging (Brody, 1955; Hender- son, Tomlinson, and Gibson, 1980). However, because several studies have indicated that brain neurons may shrink with age, which could result in artifactually reduced values for neuronal density, the interpretation that decreased neuronal density is indicative of cell loss has been questioned (Haug, 1985; Terry, De Teresa, and Hansen, 1987). On the other hand, numerous imaging and postmor-

Received August I I , 1992; accepted August 11 , 1992 Journal of Neurobiology, Vol. 23, No. 9, pp. 1247- 1260 ( 1 992) 0 1992 John Wiley & Sons, Inc. CCC 0022-3034/92/09 1247-14

tem studies have shown that brain volume also shrinks with age, to a degree that appears to more than offset the effects of neuronal shrinkage on neuronal density measures. Moreover, neocortical neurons do not necessarily shrink with age, as the size of pyramidal neuronal dendritic trees can actually increase in healthy normal aging (Buell and Cole- man, 198 1 ). Thus, even after corrections for possible neuronal shrinkage, there appears to be an overall loss of neocortical neurons with aging (Terry et al., 1987).

The problems of variability associated with differential tissue shrinkage due to age, postmortem delay, immersion fixation artifact, and individual aging differences make reliable counts of neuronal density in human neocortex extraordinarily difficult. However, in well-defined structures for which the overall volume can also be measured, cell counts are generally more reliable. Such studies have shown that whereas many subcortical nuclei

1247

1248 Landfield et ul.

do not lose neurons with aging, several monoamin- ergic nuclei are substantially affected by cell loss (Brody, 1978). Interestingly, a recent count of neurons throughout the entire human hippocampus, using new unbiased stereological methods that are not affected by cell size, found a clear age-related loss of pyramidal neurons in field CA 1 (West and Gunderson, 1990). However, the sample size in that study was relatively small, and the authors note the need for additional data on this question.

Animal studies usually allow fixation artifacts to be controlled more effectively, and studies in animal models of aging have also found that some, but certainly not all, brain regions lose neurons with aging (Coleman and Flood, 1987). Although some of these results are also controversial, the data for field CA 1 in the hippocampus are highly consistent and essentially all studies in rodents have found age-related decreases in CA 1 neuronal density ( Landfield, Baskin and Pitler, 198 I ; Landfield, 1987a; Kerr, Campbell, Applegate, Brodish, and Landfield, 199 1 ; see review in Coleman and Flood, 1987).

With regard to Alzheimer’sdisease, there is widespread agreement that neocortical and hippocampal (primarily CA 1 ) neurons degenerate and are lost in substantial numbers as AD progresses (Mann, 1985; Terry, Peck, IIeTeresa, Schechter, and Horoupian, 198 1; Buell and Coleman, 198 1 ). However, one of the key questions regarding age- associated neuronal death is whether neuronal loss in AD is related at the mechanistic level to neuronal loss in normal brain aging. Clearly, this issue has major implications for our strategies in at- tempting to understand the bases of both AD and normal brain aging. Although this question cannot be answered definitively at this point, there is substantial evidence of a fundamental link of some kind between normal brain aging and AD. Aspects of this evidence are summarized briefly below.

PATHOGENESIS OF AGE-ASSOCIATED NEURODEGENERATION IN ALZHEIMER’S DISEASE

Hypotheses on the etiology/pathogenesis of Alz- heimer’s disease have suggested possible roles for infectious agents (Wisniewski and Merz, 1985; Prusiner, 1987 ) , environmental toxins (Perl, 1985; Ehmann, Markesbery, Alauddin, et a]., 1986; Calne, Eisen, McGeer, and Spencer, 1986), abnormal protein regulation, particularly with regard to beta amyloid and tau proteins (Iqbal,

Grundke-Iqbal, and Wisniewski, 1987; Selkoe, 1989; Kosik, 1990), loss of trophic factors (Hefti, Hartikka, and Knusel, 1989), changes in membrane structure (Markesbery, Leung, and Butter- field, 1980; Pettegrew, Moosy, Withers, McKeag, and Panchalingam, 1988a, Pettegrew et al., 1988b), impairedenergy metabolism due to micro- vasculature changes ( Khachaturian, Radebaugh, and Monjan, 1490), or generalized metabolic disturbances (Sims, Finegan, and Blass, 1987; Hoyer, Oesterreich, and Wagner, 1988), as well as roles for other factors (cf. reviews in Khachaturian et al., 1 990; Katzman and Saitoh, I99 1 ; Whitehouse, 1986). In addition, there is evidence that genetic factors contribute to at least some forms of A D (Schellenberg et al., 1987; Roses, 1989). However, although there are findings supporting each of these views, none of these processes has yet been implicated definitively in the initial pathogenesis of AD. Moreover, few if any of these hypotheses are incompatible with other hypotheses, since AD appears to be a complex, potentially multietiologi- cal phenomenon (cf. above) that could involve in- teractions among a number of factors.

LINKAGE BETWEEN NORMAL BRAIN AGING AND AD

Any hypothesis of AD has to account for increasing evidence suggesting that almost everyone who lives long enough may eventually become a victim of AD; that is, it is now clear that previous esti- mates of Alzheimer’s disease incidence have been substantially on the low side, and that nearly 50% of those over age 85 may have some form of AD (see Evans et al., 1989). In fact, a recent summary of studies on the incidence of AD shows that AD increases exponentially after age 60-65, and extrap- olation of the incidence curve in that paper suggests that nearly everyone who lives to 105-1 10 years of age might develop some form of AD (cf. Fig. 1 in Katzman and Saitoh, 1991). These re- markable figures indicate that AD is so widespread that its causative factors may be almost as universal as the aging process itself‘. Moreover, the brains of all individuals over age 80 contain at least some histological hallmarks of AD-plaques, tangles, and neuron loss (Matsuyama, Namicki, and Wa- tanabe, 1966)-and there is much less difference between the brains of the “normal” elderly and AD subjects after age 80 than there is before age 65

Neuronul Deuth in Bruin Aging 1249

(due to continuing brain changes in the clinically normal individuals) (Gottfries, 1988; Mann, 1985). In humans, the patterns of normal brain aging fairly closely mimic those of AD qualita- tively, in that basically all properties of neuropathology seen in AD are present-albeit in substantially lesser numbers-in the brains of the clinically normal elderly (Wisniewski and Terry, 1973; Wisniewiski and Merz, 1985; Katzman and Saitoh, I99 1 ) . Thus, any factor that was able somehow to induce dramatic quantitative increases in normal brain aging processes apparently would convert normal brain aging to the same condition as AD.

These observations suggest both that aging is the primary “risk factor” for AD (cf. Katzman and Saitoh, 1991), and that brain cell loss with aging may be a good model for cell loss in AD. The corol- lary of this latter conclusion seems to be that if animal models of aging are relevant to normal human aging, then they are also likely to be relevant to AD neurodegeneration.

Aging rodent brains do not develop plaques and tangles; however, most recent studies suggest that loss or shrinkage of neurons, dendrites, and/or synapses is more closely correlated with either dementia or aging than are plaques and tangles (cf. Terry et al., 1987, 1990; Buell and Coleman, 1979; Scheff, DeKosky, and Price, 1990). As noted above, it is clear that aged rodents exhibit pyramidal cell loss in hippocampus (Landfield et a]., 198 1; Landfield, I987a; Kerr et al., 199 1 ) as well as cell loss or dendritic/synaptic changes in some, but not all other brain regions (Coleman and Flood, 1987; Geinisman, De Toledo-Morrell, and Mor- rell, 1986). Moreover, aging rodents exhibit extensive hippocampal astrocyte hypertrophy (Land- field et al., 1977, 1978; Geinisman, Bondareff, and Dodge, 1978) just as do aging humans (Wis- niewski and Terry, 1973; Hansen, Armstrong, and Terry, 1987).

Thus, there seems to be an extremely close association between normal brain aging processes and age-correlated neurodegenerative diseases such as AD. Moreover, the loss of neurons in field CA 1 of the hippocampus is a consistent correlate of aging across species, and is also prominent in human AD. For these reasons, we have focused on cellular mechanisms of dysfunction and pathology in hippocampal CA 1 neurons in aging rats as models for more general mechanisms of brain aging and, possi- bly AD. Some implications of these studies, and those of others, for putative cellular mechanisms of age-associated cell loss are outlined below.

EVIDENCE FOR AN AGING- ASSOCIATED SUSCEPTIBILITY FACTOR( S)

The extremely widespread susceptibility to AD observed in aging humans who live long enough (Katzman and Saitoh, 1991) suggests that some normal physiological aging process may inexor- ably and systematically increase vulnerability to AD-associated neuronal death. Recent studies from this laboratory have also found evidence that aging increases the vulnerability of brain neurons to other neurodegenerative influences. In a study in which mild but chronic (6 months) stress was administered to rats of three different age groups, only the aged-stressed animals exhibited increased neuronal loss in field CA 1 of the hippocampus, in comparison to nonstressed controls (Kerr et al., 199 1 ). This chronic stress paradigm also resulted in a decrease of hippocampal corticosterone receptors, which was less in the aged animals (Eldridge, Kute, Brodish, and Landfield, 1989), suggesting that the aging-associated resistance to down-regulation might have increased neuron vulnerability to the neuropathologic effects of elevated glucocorticoids.

Thus, in conjunction with the clear age dependence of Alzheimer’s disease (and several other neurodegenerative disorders), these and other animal data imply that there is an aging-associated susceptibility factor that increases the probability of cell death in the presence of neurotoxic conditions.

This possibility does not in itself explain why some individuals are susceptible to neurodegenerative disease at much younger ages than are others. Conceivably therefore, it is in the area of individual variation in the development of AD that some of the several hypotheses of AD involving environmental toxins, infectious agents, genetic predispo- sition, or other nonaging factors may be particularly relevant. However, it also seems of key impor- tance to define the apparent universal aging process (with which such extraneous factors may interact ) that underlies the increasing susceptibility to cell loss. Further, individual variation in the rate of progression of aging processes may also contribute to individual variability in neuronal susceptibility.

Unlike AD, there are relatively few testable etiological hypotheses to account for normal brain aging. Two of the current views on brain aging are the “altered calcium (Ca2+ ) homeostasis” hypothesis and the “cumulative glucocorticoid- (GC) induced

1250 Landfield et a1

neurodegeneratiorz” hypothesis. Recently, these have been linked by experimental evidence into a single, multiphase hypothesis ( Kerr, Campbell, Hao, and Landfield, 1989). The evidence supporting these concepts is outlined further in the following sections.

EVIDENCE FOR CALCIUM DYSHOMEOSTASIS IN BRAIN AGING/ ALZHEIMER’S DISEASE

There is increasing recognition of the substantial neurotoxic potential associated with dysregulation of cellular calcium ( Ca2+) homeostasis. Dysregu- lated elevations of intracellular Ca2+ concentration have been implicated in ischemic damage to car- diac and neural tissues for more than a decade (Schlaepfer and Hasler, 1979; Nayler, Poole-Wil- son, and Williams, 1979; Siesjo, 198 1 ) . Ca2+ channel blockers are under intensive study for potential protective uses in stroke and ischemic heart damage (Scriabine, Schuurman, and Traber, 1989). In addition, in vivo and tissue culture studies have implicated excess Ca2+ influx as a key element in amino acid excitotoxicity (cf. reviews in Rothman and Olney, 1987; Choi, 1987: Mattson, Murrain, Guthrie, and Kater, 1989).

Nevertheless, it is only recently that Ca2+ dysregulation has been suggested to play a role in neurodegenerative diseases associated with aging. In the early to mid 1980s, several lines of evidence pointed to altered Ca2+ regulation as a highly consistent concomitant of brain aging in rodents (cf. Gibson and Peterson, 1987; Michaelis, Johe, and Kitos, 1984; Landfield and Pitler, 1984; Landfield, Pitler, and Applegate, 1986). ‘These and other studies in a few laboratories led to the formal suggestion that changes in neuronal Ca’” homeostasis might be a key final pathway in age-related brain decline (cf. Khachaturian, 1984, 1989; Gibson and Peter- son, 1987; Landfield, 1987b).

Over the past years, electrophysiological studies in our laboratory have found aging-dependent alterations of Ca2+ -mediated potentials and currents in neurons of aged hippocampus in rats, indicative of age-related changes in voltage-activated Ca2+ channels (see review in Landfield, Campbell, Hao, and Kerr, 1989). An overview of these results is presented below. In addition, evidence has been obtained by others of altered Ca2+ extrusion, buff- ering or uptake in neurons from aged rat brain and reduced clearance of Ca2+ from aged rat neuromuscular terminals (Michaelis et al., 1984; Smith,

1988; Martinez-Serrano, Blanco, and Sastrustegui, 1992; see reviews in Gibson and Peterson, 1987; Khachaturian, 1089). Similar observations have been made in other excitable tissues (cf. Roth, 1988). Furthermore, Ca2+ channel antagonists are highly effective in counteracting age-associated be- havioral decline ( Deyo, Straube, and Disterhoft, 1989; Scriabine, et al., 1989).

Apart from animal studies, environmental / epi- demiologic studies of the indigenous Chamarro people of Guam, and of populations in the %i Peninsula of Japan and southern West New Guinea (all of whom have an extraordinarily high incidence of degenerative amyotrophic lateral sclerosis and Parkinson-dementia ( ALS-PD) in comparison to Western populations), have found low magnesium and calcium in the drinking water of these regions. Yase ( 1979) and colleagues have hy- pothesized that the low calcium/ magnesium in the diet could result in elevated parathyroid hormone (PTH) activity, which, in turn, would mobilize calcium from the bone and result in excessive calcifi- cation of and/or aluminum uptake into soft tissues, including central nervous system. These in- vestigators have found that PTH is elevated in affected individuals, and almost twice the concentration of Ca was present in brains of demented patients at autopsy (Yase, 1979). Moreover, Perl, Gajdusek, Garruto, Yanagihara, and Gibbs ( 1982) found that degenerating neurons from ALS-PD subjects, as well as from western AD subjects, contain higher Ca2+ and aluminum than did nonaf- fected neurons, which could be related to disorders of Ca2+ metabolism.

A more recent suggestion on the cause of brain degenerative disease in Guam is the presence of a toxic excitatoiy amino acid (EAA) in the diet (Spencer et a1 , 1987). Elevated activity of EAAs has also been postulated to underlie Alzheimer’s disease (Greenmayre and Y oung, 1989). Neverthe- less, EAAs are also believed to cause “excitotoxic” neural damage by increasing intracellular calcium (Rothman and Olney, 1987; Choi, 1987). Thus, one cofactor necessary for toxic EAA actions might be the presence of altered calcium homeostasis or increased membrane permeability to calcium (which would enhance the impact of EAA stimula- tion). Further data implicating altered Ca2+ homeostasis in the neuronal damage in AD has come from studies in which EAAs and calcium iono- phores induced neurofibrillary tangle-like antigenic changes in cultured hippocampal neurons (Mattson, 1990).

There also have been a number of studies exam-

Neuronal Death in Brain Aging 1251

ining peripheral Ca2+ regulation specifically in AD subjects. Most of these have been inconclusive, although the possibility that AD might be associated with a general systemic defect in Ca2+ regulation was raised by studies of Ca2+ uptake in cultured fibroblasts from AD subjects (Peterson, Gibson, and Blass, 1985). Further, a recent study found clear evidence of altered serum Ca2+ / phosphate balance in the first stages of AD, in healthy outpa- tient subjects with no vascular complications (Landfield, Applegate, Schmitzer-Osborne, and Naylor, I99 1 ).

There is also increasing evidence that a number of key Ca2+ regulatory proteins, including the Ca2+ binding protein, Calbindin-28k (Iacopino and Christakos, 1990a), the Ca2+/calmodulin-dependent kinase I1 ( McKee, Kosik, Kennedy, and Ko- wall, 1990), and protein kinase C (PKC) (Masliah, Cole, Hansen, Mallory, Albright, Terry, and Sai- toh, 1991; Saitoh, Masliah, Jin, Cole, Wieloch, and Shapiro, 199 1 ) are altered in the brains of AD subjects. In addition, increased protease activity appears to be a highly consistent correlate of AD-related neuritic plaques (Cataldo and Nixon, 1990), and some increased protease activity during aging or AD may also be associated with Ca2+-activated proteases (calpains) (Nilsson, Alafuzoff, Blennow, et al., 1990; Lynch, Larson, and Baudry, 1986).

Clearly, such changes in Ca2+ channels, Ca2+ regulatory proteins, or Ca2+-dependent second messengers with aging and/ or age-associated neurodegenerative disease seem to be potential candidate mechanisms for the aging-associated susceptibility factor( s ) discussed above. However, it will now be critical to define specifically which, if any, of these changes in Ca2+ regulation are most important from an etiological /pathogenetic prospec- tive.

EVIDENCE OF AGE CHANGES IN VOLTAGE-ACTIVATED CALCIUM CHANNELS

Although there appears to be a number of potential sites of altered Ca2+ homeostasis in aging neurons, our own electrophysiological studies have pointed to a specific potential source of dysregulated or elevated neuronal Ca2+, namely, voltage-activated Ca2+ influx. These studies initially focused on synaptic function (Landfield and Morgan, 1984; Landfield et al., 1986), but subsequently, have been directed toward measures of voltage-activated Caz+ influx in the soma.

The Ca2+-dependent, potassium (K+)-mediated afterhyperpolarization ( AHP) that follows sodium ( Na+ ) action potentials in hippocampal neurons is directly dependent on Ca2+ influx (Alger and Nicoll, 1980; Hotson and Prince, 1980). In a series of quantitative intracellular recording studies in hippocampal slices, we found that this AHP is consistently larger and more prolonged in CA 1 neurons from aged than from young mature rats (Landfield and Pitler, 1984; Kerr et al., 1989) (Figure 1). Moreover, in recent pharmacological studies, nimodipine, a specific blocker of L-type Ca2+ channels (Scriabine et al., 1989) was found to block the AHP; conversely, BAY K 8644, an L-channel agonist, prolonged the AHP (Maz- zanti, Thibault. and Landfield, 1992) (Figure 2). In single-channel studies, BAY K 8644 prolongs L-channel opening and tail currents after a com- mand step (Plummer, Logothetis, and Hess, 1989). Thus, these and other studies in our laboratory have pointed specifically to the L-type of Ca2+ channel as at least one key site of aging-associated change in Ca2+ channel function.

Nevertheless, the AHP is an indirect measure of voltage-activated Ca2+ influx, and in order to study Ca2+ influx more directly, Ca2+ action potentials and Ca2+ currents were studied in CA 1 neurons in which Na+ and K + channels are blocked by specific toxins. In current clamp studies of CA 1 neurons treated with tetrodotoxin (TTX) and cesium (Cs), a large Ca2+ action potential (spike) of 200- 300 ms duration can be elicited by intracellular current injection. The Ca2+ action potential is gen- erated by inward Ca2+ currents and consists of a sharp spike phase, followed by a long "hump" or plateau (Pitler and Landfield, 1987). The hump phase is apparently also mediated by prolonged L- type Ca2+ currents, as it is highly sensitive to both nimodipine and BAY K 8644.

This Ca2+ action potential is also dramatically and consistently larger in CA1 neurons of hippocampal slices from aged rats (Pitler and Landfield, 1990). Both the AHP and the Ca2+ spike results have been studied quantitatively and replicated in several studies.

Voltage-clamp studies in adult neurons are more difficult to perform quantitatively because of space-clamp problems and extreme variability in current amplitude as a function of cell size. Most patch-clamp preparations involve embryonic cells or dissociated neurons from young animals. How- ever, we have been able to conduct voltage-clamp studies of Ca2+ currents in CAI neurons of aged and adult rats, using discontinuous sharp electrode

1252 Landfield ct a1.

A

B

’ 1 R

n

L * il

n I

Figure 1 Intracellular current-induced bursts of action potentials and subsequent after hyper- polarizations in CAI neurons of hippocampal slices from young and aged rats. (A) AHP following a 0.4-nA current-induced burst of two spikes. (A,) Cell from a young rat. (A2) Cell from an aged rat. ( H ) AHP and concomitant conductance increases following a 0.4-nA current-induced burst of three spikes. ( B, ) Young rat cell in normal Ca2+ (B,) Aged rat cell in normal Ca2’. (B3) Young rat cell in low Ca2+; high Mg2+. (B4) Yciung rat cell in high Ca2+; low Mg”. Dashed lines show resting potentials before the burst. At the bottom are shown the initial intracellular depolarizing current pulse used to induce a spike burst and the subsequent 2-Hz train of 0.4-nA hyperpolarizing pulses used to assess input conductance during the AHP, for cells shown in (B) . (Reprinted from Landfield and Pitler, 1984 with permission.)

voltage-clamp methods in hippocampal slices. These studies also indicate that L-type Ca2+ currents, at least, are larger in CAI neurons from aged rats. (Campbell, Hao, Thibault, and Land- field, 1989).

Thus, it seems clear that in one mammalian species, aging is associated with greater voltage-activated influx of Ca2+ through long-opening L-type channels. Although these data do not preclude a significant role for age changes xn other Ca2+ channels or Ca2+ regulatory systems, an excess Ca2+ influx through long-opening L (channels following every Na+ action potential, could clearly result in chronic, albeit moderate, elevation of intracellular Ca2+ in aged neurons.

SECOND MESSENGER REGULATION OF Ca2+ CHANNELS

If Ca” currents are increased with aging, then one obvious next question is what factors cause this increase. There is growing evidence that some aspects of Ca2’ channel activation depend on phosphorylation, whereas Ca2+-dependent inactivation of Ca2+ current, conversely, may be regulated by protein dephosphorylation; that is, inactivation and “washout” of Ca2+ current can be slowed by cyclic AMP, ATP, and/or the catalytic subunit of CAMP-dependent protein kinase A (PKA) (Byerly and Hagiwara, 1982; Fedulova, Kostyuk, and Veselosky, 1985; Armstrong and

Ncuronal Death in Brain Aging 1253

50 1 mV n A L 250 MS

Figure 2 Three intracellular traces from the same CAI neuron, showing the Ca*+-dependent slow AHP elicited by four action potentials in a young animal. The second trace was recorded 10 min after application of the Ca*+ channel blocker nimodipine ( 2 p M ) , and the third trace was recorded 10 min after application of the calcium channel agonist BAY K 8644 ( 2 p M ) . The bottom trace shows the depolarizing current pulse used to elicit four APs. Nimodipine clearly reduces the Ca2'-dependent AHP, whereas subsequent treatment with BAY K 8644 restores the AHP. The APs are clipped by the computer sampling rate. (Reprinted from Mazzanti et al., I99 1 with permission.)

Eckert, 1987). As well, P-adrenergic agonists both slow the rate of inactivation of Ca2+ current in myocardial cells and increase CAMP-dependent phosphorylation of Ca2+ channels (Bean, No- wycky, and Tsien, 1984). Experimental enhance- ment of protein kinase C inhibits both N+-like Ca2+ currents and persistent K+ current in dissociated hippocampal neurons. This inhibitory effect was reversible by the protein kinase inhibitor, H-7 (Doerner, Pitler, and Alger, 1988). Ca2+-dependent AHPs and K+ currents also are blocked by PKC (Malenka, Madison, Andrade, and Nicoll, 1986; Werz and MacDonald, 1987).

Although CAMP-mediation of Caz+ currents has been described in invertebrate cells or peripheral mammalian neurons (Gross and MacDonald, 1989), it is not clear that similar modulation occurs in brain cells. However, recent studies in our

laboratory also implicate CAMP-dependent phosphorylation in hippocampal Ca2+ currents. Inclu- sion of 1-25 mMdibutyry1 CAMP in a sharp electrode used for voltage-clamping CA 1 neurons from adult rats, substantially increased Ca2+ currents, in comparison to control cells (Thibault, Campbell, and Landfield, 1991). Moreover, this effect was reduced in CA 1 neurons from aged rats, indicating that with aging, Ca2+ channels might already be excessively phosphorylated (Thibault, Campbell, and Landfield, 1992).

In addition, only lately has it been recognized that PKA can also modulate receptor-operated channels. It was recently found that the catalytic subunit of PKA inhibited y-aminobutyric acid- (GABA) evoked single-channel currents in out- side-out patches from mouse spinal cord neurons. This reduction was prevented by inclusion of the

kinase inhibitor. PKIP in the pipette (Porter, Twy- man, Uhler, and MacDonald, 1990). In addition, postsynaptic CAMP can modulate conductance at both excitatory and inhibitory synapses ( Wolszon and Faber, 1989). Thus, if aging-dependent alterations in second messenger phosphorylating systems occur, then these might well have the capacity for extensive disturbances of a wide range of receptor- and voltage-activated ion channels, and consequently, the capacity for substantial disruption of intracellular Ca2+ regulation. Therefore, these systems are strong candidates for a role in age-related changes in Ca2+ channel function. Again, however, the question arises of what factors might induce changes in second messenger or other mediating systems.

EVIDENCE FOR GLUCOCORTICOID- MEDIATED NEUROTOXICITY IN BRAIN AGING-ASSOCIATED NEURODEGENERATION

Another current hypothesis of brain aging is that of cumulative glucocorticoid-dependent neurodegeneration. This idea arose from studies showing that long-term interventions that altered plasmacortico- steroids could alter the rate of age-related changes in the structure of the mammalian hippocampus; that is, it has been found that plasma corticosteroid levels correlate with morphological measures of hippocampal aging ( Landfield, Waymire, and Lynch, 1978) and that long-term manipulation of plasma corticosteroids can retard (e.g., by adrenalectomy) ( Landfield et al., 198 1 ; Landfield, 1987a) or accelerate (e.g., by corticoid administration or chronic stress) (Sapolsky, Krey, and McEwen, 1986; Kerr et al., 1991; Meaney, Aitken, Bhatna- gar, Van Berkel and Sapolsky, 1988) quantitative indices of brain aging (e.g., hippocampal neuron loss, glial cell reactivity). The hippocampus is particularly rich in corticosteroid receptors ( McEwen, de Kloet and Wallach, 1986), and, as noted earlier, is particularly susceptible to age-related deteriora- tion in both humans (Wisniewski and Terry, 1973; Mann, 1985) and animals (Laindfield et al., 1977, 1978; Landfield, Sundberg, Smith, Eldridge, and Moms, 1980).

Such findings have led to the hypothesis that there is a glucocorticoid-dependent component of brain aging. In this hypothesis, endogenous corticosteroids (CORT), even at normal levels, exert a gradual and cumulative degenerative effect on brain neurons, perhaps as a byproduct of some

other advantageous actions ( Landfield, 1987a; Landfield et al , 1978, 1980, 198 1 ; Sapolsky, Krey, and McEwen, 1986; McEwen et al., 1986; cf. Landfield and Eldridge, 199 1 ) . However, the mechanism of glucocorticoid-induced neurotoxicity during aging, does not seem to be similar to that underlying glucocorticoid-mediated apoptosis in lymphocytes (Compton and Cidlowski, 1986), because GC-dependent toxicity in neuronal cell culture was not associated with endonuclease-mediated DNA cleavage (Masters, Finch, and Sa- polsky, 1989).

Moreover, in recent years it has become clear that there are iIt least two types of corticosteroid receptor in the hippocampus, type I and type I1 (also termed nrineralocorticoid and glucocorticoid receptors, respectively) (Reul and deKloet, 1985). Recent studies have found that the type41 glucocorticoid receptors in the brains of aged rats are changed, such that they exhibit a higher affinity for CORT (Landfield and Eldndge, 1989). As well, these receptors are more resistant to down-regulation, and therefbre, may be in higher concentration in the hippocampus (Eldndge et a]., 1989). As noted, a recent study showed that chronic moderate stress increased hippocampal cell loss in aged rats, but not in young rats (Kerr et al., 1991). Thus, these changes in glucocorticoid receptors could increase the impact of CORT on brain cells, and, therefore, clearly seem to be candidates for an aging-associated susceptibility factor.

ALTERED ENDOCRINE REGULATION OF NEURONAL CALCIUM HOMEOSTASIS: AN INTEGRATIVE PHYSIOLOGICAL HYPOTHESIS OF NEURONAL DEATH IN AGING/ ALZHEIMER’S DISEASE

The lines of evidence for GC involvement and for Ca2+ dysregulatnon in brain aging have developed separately over more than a decade, with little indi- cation that the Iwo phenomena might be related. However, based on these two developing themes, the possibility seemed to exist that GCs might somehow mediate brain aging processes by effect- ing neuronal Ca ’+ regulation. We, therefore, tested this hypothesis by assessing the effects of adrenalectomy and CORT replacement on the Caz+ -dependent AHP (Kerr et al., 1989).

Although elucidating the physiological fhnc-

Neuronul Death in Bruin Aging 1255

tions of GC receptors in brain cells has proved highly elusive (cf. McEwen et al., 1986), our laboratory and another recently reported simulta- neously that a major effect of GCs on brain cells is to increase the Ca2+-dependent AHP (Joels and de Kloet, 1989; Kerr et al., 1989). Moreover, and perhaps most striking, the effect of GCs on the AHP was substantially greater in brain cells from aged rats; that is, following adrenalectomy, the AHP in aged neurons was reduced proportionately more than in young rat neurons (Kerr et al., 1989). This is consistent with the studies noted above on type- I1 GC receptors suggesting that the neuronal impact of GCs may increase with aging (perhaps accel- erating the neurotoxic effects of glucocorticoids) . However as noted, an effect of CORT on the Ca2+- dependent, K+-mediated AHP is not necessarily reflective of an effect on voltage-activated Ca2+ influx. The effect could instead occur through actions on K + channels or Ca2+ extrusion processes, among others. Consequently, it was important to study Ca2+ influx directly in neurons with Na+ and K + channels blocked.

EFFECTS OF GCs ON Ca2+ ACTION POTENTIALS AND CURRENTS IN CA1 NEURONS

Figure 3 shows examples of Ca2+ action potentials recorded from TTX-treated, Cs-loaded CA 1 neurons of a young, mature animal that had been adre- nalectomized ( ADX) several days earlier. Ca2+ action potentials were dramatically increased by RU 28362, a highly specific type-I1 GC receptor agonist. The last panel shows that cycloheximide can block the effect of RU 28362 in ADX animals, suggesting protein synthesis is involved in the effect of GCs on the Ca2+ spike potential (Kerr, Campbell, Thibault, and Landfield, 1992).

The quantitative results for these studies of Ca2+ action potentials were obtained from cells treated with either vehicle ( n = 19), RU28362 ( n = 30), or RU 28362 + cycloheximide ( n = 12). Drugs were applied to slices for 2-4 h before recording. All mea- surements were made at a holding potential of -70 mV. The Ca2+ action potential hump amplitude, spike width, and overall area were significantly greater in slices treated with RU 28362. Similar results were observed in quantitative analyses of Ca2+ currents using sharp electrode voltage-clamp methods. These data, therefore, provide direct evi-

n ADX + RU28362

ADX + RU28362 + Cycloheximide

_ - - - _

n 25 1 mvL nA -1. 100 ms

Figure 3 Representative Ca2' action potentials from CsCI-loaded, TTX-treated neurons in hippocampal slices that were exposed to either vehicle, the glucocorticoid receptor ligand RU 28362 (RU) or RU + cycloheximide, a protein synthesis inhibitor. Action potentials were triggered by depolarizing constant-current pulses and have an initial large-amplitude, fast phase, and a late slow phase. Neurons exposed to a saturating dose of RU exhibited wider initial phases, and longer duration and larger amplitude slow phases than control neurons. Co- incubating RU-treated slices with I0 pLM cycloheximide eliminates the effect of RU on the Caz+ action potential. (Reprinted from Kerr et al., 1992, with permission.)

dence that GCs modulate Ca2+ currents and that a genomic mechanism may be involved (Kerr et al., 1992).

The endocrine regulation of serum Ca2+ concentration has been relatively well understood for many years; however, only recently has it become clear that endocrine processes may also regulate Ca2+ homeostasis at the level of the brain neuron. Based on the above findings, some of the stronger evidence for endocrine regulation of brain cell Ca2+ homeostasis at present appears to exist for the glucocorticoids, which are perhaps not usually thought of as primary regulators of Ca2+ homeostasis in the periphery (although GC treatment has

1256 Landfield et a/.

been among the main therapies for hypercalce- mia). Further evidence in this regard is associated with the vitamin D-dependent Ca2+ binding protein (CaBP), calbindin-D,,,, which is also found in hippocampal and neocortical neurons (Baim- bridge, Miller, and Parkes, 1082; Celio, 1990). Somewhat surprisingly, in the brain, CaBP synthesis or up-regulation is not vitamin D dependent (Hall and Norman, 199 1 ), but rather appears to be regulated by glucocorticoids ( Iacopino and Chris- takos, 1990b).

CONCLUSIONS

The studies outlined above provided important support for the hypothesis that excess GC activation and Ca2+ dysregulation might be two phases of the same age-related neurodegenerative process. Specifically, these studies have tested the key pre- diction that GCs modulate Ca’+ influx in hippocam pal neurons. Moreover, the evidence that the impact of GCs on Ca2+-mediated processes in- C Y ~ U S ~ S with aging (Kerr et al., 1989) suggests that some aging change in the “bias” of this pathway might play a role in the increasing susceptibility of neurons to degeneration that occurs with aging. In addition, the findings that CAMP modulation of Ca currents is also affected by aging in hippocampal neurons (Thibault et al., 1992) and that the GC effect on the Ca2+ potential is cycloheximide sensitive (Kerr et al., 1992) suggests that GCs may modulate L-type Ca2+ channels through the regulation of second messenger phosphorylating systems.

Of course, much work remains before these phenomena might be viewed as probable mechanisms underlying aging and/or AD-associated neuronal death. Further, many other specific and general questions remain to be resolved, including whether aging-associated neuronal necrosis is somehow related mechanistically to the programmed cell death that occurs during development (cf. Oppen- heim, 199 1 ) . Nevertheless, steadily increasing evidence points to some alteration in the endocrine modulation of neuronal Ca2+ regulatory processes as a strong candidate process for a role in aging-associated susceptibility to neurodegeneration. Fur- ther studies along these lines, therefore, seem to hold considerable promise for the elucidation of fundamental mechanisms of aging-dependent brain cell death.

We thank Lisa Lowery for excellent assistance with the manuscript. Aspects of the work reviewed in this paper have been supported by grants AGO4542 and AGO7767 from the National Institute on Aging.

REFERENCES

ALGER, B. E. and NICOLL, R. A. (1980). Epileptiform burst afterhyperpolarization: Calcium-dependent potassium potential in hippocampal CA l pyramidal cells. Science 210: I 122- 1 124.

ANDERSON, K. J., DAM, D., LEE, S., COTMAN MAN, C. W. ( 1988). Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature 332:360-362.

ARMSTRONG, D. and ECKERT, R. (1987). Voltage-activated calcium channels that must be phosphorylated to respond to membrane depolarization. Proc. NatL Acud. Sci. USA 8425 18-2522.

BAIMBRIDGE, K. G., MILLER, J. J., and PARKES, C. 0. ( 1982). Calcium-binding protein distribution in the rat brain. Bruin Rex 239:519-525.

BEAN, P. B., NOWYCKY, M. C., and TSIEN, R. W. ( 1984). Beta-adrenergic modulation of calcium channels in frog ventricular heart cells. Nuturc. 307:37 I - 375.

BRODY, H. (195511. Organization of the cerebral cortex 111. A study of aging in the human cerebral cortex. J. Comp. Neurol. 1025 1 1-556.

BRODY, H. ( 1978). Cell counts in cerebral cortex and brainstem. In: Alzheimer’s Diseuse, Senile Dementia and Reluted Di.sorders (Aging Vol. 7 ) . R. Katzman, R. D. Terry, K. Bick, Eds. Raven, New York. pp. 345- 351.

BUELL, S. J . and COLEMAN. P. D. ( 198 1 ). Quantitative evidence for selective dendritic growth in normal human aging but not in senile dementia. Bruin Rex

BYERLY, L. and HAGIWARA, S. (1982). Calcium currents in internally perfused nerve cell bodies of Lymnueu stugnalis. J . Physiol. (L,ond.) 322:503-528.

CALNE, D. B., EISEN, A., MCGEER, E., and SPENCER, P. S. ( 1986). Ahheimer’s disease, Parkinson’s disease, and motoneurone disease: abiotrophic interaction between aging and environment? Lancet 2: 1067-1069.

CATALDO, A. M. and NIXON, R. A. (1990). Enzymati- cally active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc. Natl. Acud. Sci. USA 87:3861-3865.

CELIO, M. R. (1990). Calbindin D-28K and parvalbu- min in the rat nervous system. Neuroscience 35375- 475.

CHOI, D. W. ( 1987 ). Ionic dependence ofglutamate neurotoxicity. J. Neurosci. 7:369-379.

COLEMAN, P. D. and FLOOD, D. G. (1987). Neuron

214:23-4 I .

Neuronul Deuth in Bruin Aging 1257

numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol. Aging 8:52 1-545.

COMPTON, M. and CIDLOWSKI, J. ( 1986). Rapid in vivo effects of glucocorticoids on the integrity of rat lym- phocyte genomic DNA. Endocrinology 262: I 18- 138.

DEYO, R. A., STRAUBE, K. T., and DISTERHO~, J. F. ( 1989). Nimodipine facilitates associative learning in aging rabbits. Science 2435309-8 1 1.

DOERNER, D., PITLER, T. A., and ALGER, B. E. ( 1988). Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons. J. Neurosci. 8( I1):4069-4078.

EHMANN, W. D., MARKESBERY, W. R., ALAUDDIN, M., et al. ( 1986). Brain trace elements in Alzheimer’s disease. Neurotoxicology 7: 197-206.

ELDRIDGE, J. C., KUTE, T., BRODISH, A., and LAND- FIELD, P. w. ( 1989). Apparent age-related resistance of hippocampal type I1 corticoid receptors to down- regulation by chronic escape training. J. Neurosci.

EVANS, D. A., FUNKENSTEIN, H. H., ALBERT, M. S., SCHERR, P. A., COOK, N. R., CHOWN, M. J., HEBERT, L. E., HENNEKENS, C. H., and TAYLOR, J. 0. ( 1989). Prevalence of Alzheimer’s disease in a community population of older persons. JAMA 262( 18):255 1- 2556.

FEDULOVA, S. A., KOSTWK, P. G., and VESELOVSKY, N. S. (1985). Two types of calcium channels in the somatic membrane of new-born rat dorsal root gan- glion neurons. J. Physiol. (Lond.) 359:43 1-446.

GEINISMAN, Y . , BONDAREFF, W., and DODGE, J. T. ( 1978). Hypertrophy of astroglial processes in the dentate gyrus of the senescent rat. Am. J . Anat.

GEINISMAN, Y., DE TOLEDO-MORRELL, L., and MORRELL, F. (1986). Aged rats need a preserved complement of perforated axospinous synapses per hippocampal neuron to maintain good spatial memory. Brain Rex 398:266-275.

GIBSON, G. E. and PETERSON, C. (1987). Calcium and the aging nervous system. Neurobiol. Aging 8:329- 344.

GOTTFRIES, C. G. ( 1988). Alzheimer’s disease: A critical review. Comprehen. Gerontol. 2:47-62.

GREENMAYRE, J. T. and YOUNG, A. B. (1989). Excit- atory amino acids and Alzheimer’s disease. Neurobiol. Aging 10:593-602.

GROSS, R. A. and MACDONALD, R. L. ( 1989). Cyclic AMP selectively reduces the N-type calcium current component of mouse sensory neurons in culture by enhancing inactivation. J. Neurophysiol. 61:97- 105.

HALL, A. K. and NORMAN, A. W. ( 1991). Vitamin-D independent expression of chick brain calbindin- D,,,. Mol. Brain Res. 9:9-14.

HANSEN, L. A., ARMSTRONG, D. M., and TERRY, R. D. ( 1987). An immunohistochemical quantification of

9~3237-3242.

153~537-544.

fibrous astrocytes in the aging human cerebral cortex. Neurobiol. Aging 8: 1-6.

HAUG, H. ( 1985). Are neurons of the human cerebral cortex really lost during aging? A morphometric exam- ination. In: Senile Dementia ofthe Alzheimer’s Type. J. Traber and W. H. Gispen, Eds. Springer-Verlag, Berlin / Heidelberg.

HEFTI, F., HARTIKKA, J., and KNUSEL, B. ( 1989). Func- tion of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative disease. Neurobiol. Aging 10( 5 ) : 5 15- 533.

HENDERSON, G., TOMLINSON, B. E., and GIBSON, P. H. ( 1980). Cell counts in human cerebral cortex in normal adults throughout life using an image analyzing computer. J. Neurol. Sci. 46: 1 13-1 36.

HOTSON, J. R. and PRINCE, D. A. ( 1980). A calcium-activated hyperpolarization follows repetitive firing in hippocampal neurons. J. Neurophysiol. 43:409-4 19.

HOYER, S., OESTERREICH, K., and WAGNER, 0. ( 1988 ) . Glucose metabolism as the site of the primary abnor- mality in early-onset dementia of Alzheirner type? J. Neurology 235143-148.

IACOPINO, A. M. and CHRISTAKOS, S. ( 1990a). Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. Proc. Natl. Acad. Sci. USA

IACOPINO, A. and CHRISTAKOS, S. ( 1990b). Corticoste- rone regulates calbindin-D,,, mRNA and protein levels in rat hippocampus. J. Biol. Chem. 265:10177- 10180.

IQBAL, K., GRUNDKE-IQBAL, I., and WISNIEWSKI, H. M. (1987). Alterations of the neuronal cytoskeleton in Alzheimer’s disease and related disorders. In: Alter- ations in the Neuronal Cytoskeleton in Alzheimerk Disease. G. Perry, ed. Plenum Press, New York, pp.

JOELS, M. and DE KLOET, E. R. ( 1989). Effects ofgluco- corticoids and norepinephrine on the excitability in the hippocampus. Science 245: 1502- 1505.

KATZMAN, R. and SAITOH, T. ( 199 I ) . Advances in Alz- heimer’s disease. FASEB J. 5:278-286.

KERR, D. S., CAMPBELL, L. W., APPLEGATE, M. D., BRODISH, A,, and LANDRELD, P. W. ( 1991 ). Chronic stress-induced acceleration of electrophysiologic and morphometric biornarkers of hippocampal aging. J. Neurosci. 11:1316-1324.

KERR, D. S., CAMPBELL, L. W., HAO, S.-Y., and LAND- FIELD, P. W. (1989). Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science 245: 1505-1 509.

KERR, D. S., CAMPBELL, L. W., THIBAULT, O., and LANDFIELD, P. W. (1992). Hippocampal glucocorticoid receptor activation enhances voltage-dependent Ca2+ conductances: relevance to brain aging. Proc. Natl. Acad. Sci. USA 89: (in press).

87:4078-4082.

109-136.

1258 Landfield et ul.

KHACHATURIAN, Z. S. (1984). Towards theories of brain aging. In: Handbook of Studies on Psychiatry and Old Age. D. Kay and G. D. Buarrows, Eds. Else- vier, Amsterdam, pp. 7-30.

KHACHATURIAN, Z. S. ( 1989). The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging 1: 17-34.

KHACHATURIAN, Z. S., RADEBAUGH, T. S., and MON- JAN, A. A. (1990). Alzheimer’s disease: causes, controls, and cures. In: Alzheimer’s Disease: Treutment and Long- Term Management ( Neurological Diseases and Therapy: No. 4). J. Cummings, and J. Miller, Eds. Marcel Dekker, New York, pp. 275-285.

KOSIK, K. S. ( 1990). Alzheimer’s disease: a view toward the neurites. Rev. Biol. Res. Aging 4337-347.

LANDFIELD, P. W. ( 1987a). Modulation of brain aging correlates by long-term alterations of adrenal steroids and neurally-active peptides. Prog. Brain. Res.

LANDFIELD, P. W. ( 1987b). ‘Increased calcium current’ hypothesis of brain aging. Neurohiol. Aging 8:346- 347.

LANDFIELD, P. W. (1989). Calcium homeostasis in brain aging and Alzheimer’s disease. In: Diagnosis and Treatmenl of Senile Dementia M. Bergener and B. Reisberg, Eds. Springer-Verlag, Berlin, Heidelberg, pp. 276-287.

BORNE, S. E.. and NAYLOR, C. E. ( 1991 ). Phosphate/ calcium alterations in the first stages of Alzheimer’s disease: implications for etiology and pathogenesis. J. Neurol. Sci. 106:22 1-229.

LANDFIELD, P. W., BASKIN, R. K., and PITLER, T. A. ( 1981 ). Brain aging correlates: retardation by hormonal-pharmacological treatments. Science 214: 581-584.

LANDFIELD, P. W., CAMPBELL, L. W., HAO, S. -Y., and KERR, D. S. ( 1989). Aging-related increases in voltage-sensitive, inactivating calcium currents in rat hippocampus: implications for mechanisms of brain aging and Alzheimer’s disease. In: Calcium, Men?- brunes, Aging, and Alzheimer’s Diseuse. Z . s. Khachaturian, C. Cotman, and J. W. Pettegrew, Eds. Ann. N Y Acad. Sci. 568:95-105.

LANDFIELD, P. W. and ELDRDGE, J. C. (1989). In- creased affinity of type 11 corticosteroid binding in aged rat hippocampus. Exp. Neurol. 106: 1 10- 1 1 3.

LANDFIELD, P. w. and ELDRIDGE, J. c. ( I99 1 ). The glucocorticoid hypothesis of brain aging and neurodegeneration: recent modifications. Actu Endocrinol.

LANDFIELD, P. W. and MORGAN, G. (1984). Chroni- cally elevating plasma Mg2-‘ improves hippocampal frequency potentiation and reversal learning in aged and young rats. Brain Res. 322: 167- 17 1.

LANDFIELD, P. W. and PITLER, T. A. ( 1984). Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 226:1089-1092.

72:279-300.

LANDFIELD, P. w. , APPLEGATE, M. D., SCHMITZER-OS-

125354-64.

LANDFIELD, P. W., PITLER, T. A., and APPLEGATE, M. D. ( 1986). The effects of high Mgz+ to Ca2+ ratios on frequency potentiation in hippocampal slices in young and aged rats. J. Neurophysiol. 56:797-8 1 1.

LANDFIELD, P. W., ROSE, G., SANDLES, L., WOHL-

astroglial hypertrophy and neuronal degeneration in the hippocampus of aged memory-deficient rats. J. Gervntol. 32:3-- 12.

LANDFIELD, P. W., SUNDBERG, D. K., SMITH, M. S., ELDRIDGE, J. C., and MORRIS, M. (1980). Mamma- lian brain aging: Theoretical implications of changes in brain and endocrine systems during mid- and late- life. Peptides 1 ( Suppl . I ) : 1 8 5- 1 96.

LANDFIELD, P. W., WAYMIRE, J. L., and LYNCH, G. S. ( 1978). Hippocampal aging and adrenocorticoids: quantitative correlations. Science 202: 1098- 1 102.

LYNCH, G., LARSON, J., and BAUDRY, M. ( 1986). Pro- teases, neuronal stability, and brain aging: an hypothesis. In: Treatment Development Strategies For Alz- heimer’.s Diseuse. T. Crook, R. Bartus, S. Ferris, and S. Gershon, Eds. Mark Powley Associates, Madison, CT,

MALENKA, R. C., MADISON, D. V., ANDRADE, R., and NICOLL, R. A. ( 1986). Phorbol esters mimic some cholinergic actions in hippocampal pyramidal neurons. J. Neurosci. 6( 2):475-480.

MA”, D. M. A. (1985). The neuropathology of Alz- heimer’s disease: a review with pathogenetic, etiological and therapeutic considerations. Mech. Aging De- velop. 3 1 :2 1 3 -2 5 5.

MARKESBERY, W. R., LEUNG, P. K., and BUTTERFIELD, D. A. (1980). Spin label and biochemical studies of erythrocyte membranes in Alzheimer’s Disease. J. Neurol. Sci. 45323-330.

TR~STEGUI, J . (1992). Calcium binding to the cyto- sol and calcium extrusion mechanisms in intact syn- aptosomes and their alterations with aging. J. Biol. Chem. 267( 7):4672-4679.

MASLIAH, E., COLE, G. M., HANSEN, L. A., MALLORY, M., ALBRIGMT, T., TERRY, R. D., and SAITOH, T. ( 199 I ). Protein kinase C alteration is an early biochemical marker in Alzheimer’s disease. J. Neurosci.

MASTERS, J. Pi., FINCH, C. E., and SAPOLSKY, R. M. ( 1989). Glucocorticoid endangerment of hippocampal neurons does not involve deoxyribonucleic acid cleavage. Endocrinology 124( 6):3083-3088.

MATSUYAMA, H., NAMICKI, H., and WATABABE, J. (1966). Senile changes in the brain in the Japanese. Incidence of Alzheimer’s neurofibrillary change and senile plaques. In: Proceedings of the F$h Interna- tional Congress of Neuroputhology (Excerpta Medica International Congress Series No. 100). F. Luthy and A. Bischoff; Eds. Excerpta Medica, Amsterdam, pp.

MATTSON, M. P. ( 1990). Antigenic changes similar to

STADTER, T. cl., and LYNCH, G. (1977). Patterns Of

pp. 119-149.

MARTINEZ-SERRANO, A., BLANCO, P., and SA-

11 (9):2759--2767.

979-980.

Neuronal Death in Brain Aging 1259

those seen in neurofibrillary tangles are by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron 4:105-117.

MATTSON, M. P., MURRAIN, M., GUTHRIE, P. B., and KATER, S. B. ( 1989). Fibroblast growth factor and glutamate: opposing roles in the generation and degeneration of hippocampal neuroarchitecture. Neuro- sci. Res. 21:447-464.

MAZZANTI, M. L., THIBAULT, O., and LANDFIELD, P. W. ( I99 1 ). Dihydropyridine modulation of normal hippocampal physiology in young and aged rats. Neurosci. Rex Commun. 9(2):117-126.

MCEWEN, B. S., DE KLOET, E. R., and WALLACH, G. ( 1986). Adrenal steroid receptors and actions in the nervous system. Physiol. Rev. 66:1121-1188.

MCKEE, A. C., KOSIK, K. S., KENNEDY, M. B., and Ko- WALL, N. W. (1990). Hippocampal neurons predis- posed to neurofibrillary tangle formation are enriched in Type I1 calcium/calmodulin-dependent protein kinase. J. Neuroputhol. Exp. Neurol. 49( 1 ):49-63.

MEANEY, M. J., AITKEN, D. H., BHATNAGAR, S., VAN BERKEL, C. H., and SAPOLSKY, R. M. ( 1988). Postna- tal handling attenuates neuroendocrine, anatomical, and cognitive impairments related to the aged hippocampus. Science 238:766-768.

MICHAELIS, M. L., JOHE, K., and KITOS, T. E. (1984). Age-dependent alterations in synaptic membrane systems for Ca2+ regulation. Mech. Aging Dev. 252 15- 225.

NAYLER, W. G., POOLE-WILSON, P. A., and WILLIAMS, A. (1979). Hypoxia and calcium. J . Molec. Cell Cur- did. 11:683-706.

NILSSON, E., ALAFUZOFF, I., BLENNOW, K., et al. ( 1990). Calpain and calpastatin in normal and Alz- heimer-degenerated human brain tissue. Neurohiol. Aging 11:425-431.

OPPENHEIM, R. W. ( 199 I ). Cell death in the developing nervous system. Annu. Rev. Neurosci. 14:453-501.

PERL, D. P. ( 1985). Relationship of aluminum to Alz- heimer's disease. Environ. Health Perspect. 63: 149- 153.

PERL, D. P., GAJDUSEK, D. C., GARRUTO, R. M., YANA- GIHARA, R. T., and GIBBS, C. J. ( 1982). Aluminum accumulation in amyotrophic lateral sclerosis in Par- kinsonism dementia of Guam. Science 217: 1053.

PETERSON, C., GIBSON, G., and BLASS, J. P. ( 1985). Al- tered calcium uptake in cultured skin fibroblasts from patients with Alzheimer's disease. N. Engl. J. Med.

PETTEGREW, J. W., Moosu, J., WITHERS, G., McKEAG, D., and PANCHALINGAM, K. (1988a). "p Nuclear magnetic resonance study of the brain in Alzheimer's disease. J . Neuropathol. Exp. Neurol. 47:235-248.

PETTEGREW, J. W., PANCHOLINGAM, K., Moossu, J., MARTINEZ, J., RAO, G., and BOLLEN, F. ( 1988b). Correlation of phosphorus-3 1 magnetic resonance spectroscopy and morphologic findings in Alz- heimer's disease. Arch. Neurol. 45: 1093- 1096.

31 2: 1063- 1065.

PITLER, T. A. and LANDFIELD, P. W. ( 1987). Probalble Ca2+ mediated inactivation of Ca2+ currents in mammalian brain neurons. Bruin Res. 410:147-153.

PITLER, T. A. and LANDFIELD, P. W. ( 1990). Aging-related prolongation of calcium spikes in rat hippocampal slice neurons. Brain Res. 508: 1-6.

PLUMMER, M. R., LOGOTHETIS, D. E., and HESS, P. ( 1989). Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron 2: 1453- 1463.

PORTER, N. M., TWYMAN, R. E., UHLER, M. D., and MACDONALD, R. L. ( 1990). Cyclic-AMP dependent protein kinase decreases GABA, receptor current in mouse spinal neurons. Neuron 5789-796.

PRUSINER, S. B. (1987). Prions and neurodegenerative disease. N. Engl. J. Med. 316:1571-1581.

REUL, J. M. H. M. and DE KLOET, E. R. (1985). Two receptor systems for corticosterone in rat brain: micro- distribution and differential occupation. Endocrinol-

ROSES, A. D. ( 1989). A conservative viewpoint on linkage in Alzheimer's disease. Neurobiol. Aging 10:427- 429.

ROTH, G. S. ( 1988). Mechanisms of altered hormone and neurotransmitter action during aging: the role of impaired calcium mobilization. Ann. NY Acad. Sci. 521:170-176.

ROTHMAN, S. M. and OLNEY, J. W. ( 1987). Excitotoxic- ity and the NMDA receptor. Trends Neurosci.

SAITOH, T. E., MASLIAH, E., JIN, L. W., COLE, G. M., WIELOCH, T., and SHAPIRO, I. P. ( 1991). Protein ki- nases and phosphorylation in neurological disorders and cell death. Lab. Invest. 64596-616.

SAPOLSKY, R. M., KREY, L. C., and MCEWEN, B. S. ( 1986). The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocrine Rev.

SCHEFF, S. W., DEKOSKY, S. T., and PRICE, D. A. ( 1990). Quantitative assessment of cortical synaptic density in Alzheimer's Disease. Neztrobiol. Aging 11:29-37.

SCHELLENBERG, G. D., DEEB, S. S., BOEHNKE, M., BRYANT, E. M., MARTIN, G. M., LAMPE, T. H., and BIRD, T. D. ( 1987). Association of an apolipoprotein C11 allele with familial dementia of the Alzheimer type. J . Neurogenet. 4:97-108.

SCHLAEPFER, W. W. and HASLER, M. B. ( 1979). Charac- terization of the calcium-induced disruption of neuro- filaments in rat peripheral nerve. Brain Res. 168:299- 309.

SCRIABINE, A., SCHUURMAN, T., and TRABER, J. ( 1989). Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB J.

SELKOE, D. J. ( 1989). Biochemistry ofaltered brain proteins in Alzheimer's disease. Annu. Rev. Neurosci.

ogy 117:2505-25 11.

10:299-302.

7~284-30 I .

3: 1799- 1806.

12~463-490.

1260 Landfield et al.

SIESJO, B. K. ( 198 1 ). Cell damage in the brain: a specula- tive synthesis. J. Cereb. Blood Flow Metab. 1:155- 185.

SIMS, N. R., FINEGAN, J. M., and BLASS, J. P. (1987). Altered metabolic properties of cultured skin fibroblasts in Alzheimer’s disease. Ann. Neurol. 21:45 1- 457.

SMITH, D. 0. (1988). Muscle-specific decrease in pre- synaptic calcium dependence and clearance during neuromuscular transmission in aged rats. J . Neuro- physiol. 59: 1069- 1082.

SPENCER, P. S., NU”, P. B., HUGON, J., LUDOLPH, A. C., ROSS, S. M., ROY, D. N., and ROBERTSON, R. C. (1987). Guam amyotrophic lateral sclerosis- parkinsonism-dementia linked to a plant excitant neu- rotoxin. Science 2375 17-522.

TERRY, R. D., DETERESA, R., and HANSEN, L. A. (1987). Neocortical cell counts in normal human adult aging. Ann. Neurol. 21530-539.

TERRY, R. D., MASLIAH, E., SALMON, D., BUTTERS, N., DE TERESA, R., HANSEN, L. A., and KUTZMAN, R. ( 1990). Structure-function correlations in Alz- heimer’s disease. J. Neuropulho/. Exp. Neurol. 49:335.

TERRY, R. D., PECK, A,, DETERESA, R., SCHECHTER, R., and HOROUPIAN, D. S. ( 198 1 ). Some morphometric aspects of the brain in senile dementia of the Alz- heimer type. Ann. Neurol. 10: 184- 192.

THIBAULT, O., CAMPBELL, L. W., and LANDFIELD, P. W. (1991). Cyclic AMP modulation of L-type calcium currents in non-dissociated hippocampal neurons. Soc. Neurosci. Abstr. 17:9 1.

THIBAULT, O., CAMPBELL, L. W., and LANDFIELD, P. W.

( 1992). Aging differences in the cyclic AMP modulation of L-type calcium currents in hippocampal slice neurons. SOC. Neurosci. Abstr. 18: 1482.

WERZ, M. A. and MACDONALD, R. L. ( 1987). Phorbol esters: voltage-dependent effects on calcium-dependent action potentials of mouse central and peripheral neurons in cell culture. J. Neurosci. 7(6) : 1639-1647.

WEST, M. J. and GUNDERSON, H. J. G. (1990). Unbi- ased stereological estimation of the number of neurons in the human hippocampus. J. Comp. Neurol. 296:l-22.

WHITEHOUSE, P. J . ( 1986). Understanding the etiology of Alzheimer’s disease. Current Approaches Neurol. Clin. 4(2):427--437.

WISNIEWSKI, H. M. and MERZ, G. S. (1985). Neuropa- thology of the aging brain and dementia of the Alz- heimer type. In: Aging 2000: Our Health Care Des- tiny, Vol. 1: Biomedical Issues. C. M. Gaitz and T. Samorajski, Etls. Springer-Verlag, New York, pp.

WISNIEWSKI, H. M. and TERRY, R. D. ( 1973). Morphol- ogy of the aging brain, human and animal. In: Pro- gress in Brain Research. D. M. Ford, Ed. Elsevier, Amsterdam; 40:167-186.

WOLSZON, L. R. and FABER, D. S. ( 1989). The effects of postsynaptic levels of cyclic AMP on excitatory and inhibitory responses ofan identified central neuron. J. Neurosci. 9( 3):784-797.

YASE, Y . ( 1979). ALS in the Kii Peninsula: one possible etiological hypothesis. In: Amyotrophic Laterul Sclero- sis. T. Tsubaki and Y . Toyokura, Eds. Tokyo Univer- sity Press, Tokyo, 307-3 18.

231-243.

Mechanisms of neuronal death in brain aging and alzheimer's disease: Role of endocrine-mediated...

Documents

Transcript of Mechanisms of neuronal death in brain aging and alzheimer's disease: Role of endocrine-mediated...